The matrix protein Fibulin-5 is at the interface of tissue stiffness and inflammation in fibrosis.
Fibrosis is a pervasive disease in which the excessive deposition of extracellular matrix (ECM) compromises tissue function. Although the underlying mechanisms are mostly unknown, matrix stiffness is increasingly appreciated as a contributor to fibrosis rather than merely a manifestation of the disease. Here we show that the loss of Fibulin-5, an elastic fibre component, not only decreases tissue stiffness, but also diminishes the inflammatory response and abrogates the fibrotic phenotype in a mouse model of cutaneous fibrosis. Increasing matrix stiffness raises the inflammatory response above a threshold level, independent of TGF-β, to stimulate further ECM secretion from fibroblasts and advance the progression of fibrosis. These results suggest that Fibulin-5 may be a therapeutic target to short-circuit this profibrotic feedback loop.
Nakasaki, M; Hwang, Y; Xie, Y; Kataria, S; Gund, R; Hajam, EY; Samuel, R; George, R; Danda, D; M J, P; Nakamura, T; Shen, Z; Briggs, S; Varghese, S; Jamora, C
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